6H8S
CRYSTAL STRUCTURE OF THE MOUSE PROTEIN TYROSINE PHOSPHATASE PTPN5 (STEP) IN COMPLEX WITH COMPOUND BI-0314
Summary for 6H8S
| Entry DOI | 10.2210/pdb6h8s/pdb |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 5, 1-[3-piperidin-4-yl-5-(trifluoromethyl)phenyl]guanidine (3 entities in total) |
| Functional Keywords | protein phosphatase, ptn5, step, allosteric modulator, hydrolase |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 35166.87 |
| Authors | Fiegen, D.,Schnapp, G. (deposition date: 2018-08-03, release date: 2018-09-26, Last modification date: 2024-01-17) |
| Primary citation | Tautermann, C.S.,Binder, F.,Buttner, F.H.,Eickmeier, C.,Fiegen, D.,Gross, U.,Grundl, M.A.,Heilker, R.,Hobson, S.,Hoerer, S.,Luippold, A.,Mack, V.,Montel, F.,Peters, S.,Bhattacharya, S.,Vaidehi, N.,Schnapp, G.,Thamm, S.,Zeeb, M. Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule. J. Med. Chem., 62:306-316, 2019 Cited by PubMed Abstract: Protein tyrosine phosphatase non-receptor type 5 (PTPN5, STEP) is a brain specific phosphatase that regulates synaptic function and plasticity by modulation of N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Dysregulation of STEP has been linked to neurodegenerative and neuropsychiatric diseases, highlighting this enzyme as an attractive therapeutic target for drug discovery. Selective targeting of STEP with small molecules has been hampered by high conservation of the active site among protein tyrosine phosphatases. We report the discovery of the first small molecule allosteric activator for STEP that binds to the phosphatase domain. Allosteric binding is confirmed by both X-ray and N NMR experiments, and specificity has been demonstrated by an enzymatic test cascade. Molecular dynamics simulations indicate stimulation of enzymatic activity by a long-range allosteric mechanism. To allow the scientific community to make use of this tool, we offer to provide the compound in the course of an open innovation initiative. PubMed: 30207464DOI: 10.1021/acs.jmedchem.8b00857 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.771 Å) |
Structure validation
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